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Lecture

BIOL 314- Definitions (Duchaine section)

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Department
Biology (Sci)
Course
BIOL 314
Professor
Thomas Duchaine
Semester
Fall

Description
Definitions: RNA interference RNAi Type of gene regulation. Involves trigger dsRNA (may be from virus) In C. elegans: Potent, Specific, Systemic, Inheritable. Can also be seen in mammalian cells. miRSC recruits deadenylase to remove poly-A tail which stabilises mRNA, preventing degradation. Reduced half-life andreduction in translation initiation. In mammals this is coupledwith decapping. siRNA Unit responsible for interference in the RNAi pathway Argaunaute Catalytic components of RISC complex Piwi domain Found in argonaute, responsible for SLICER activity. Slicer Activity which results in mRNA degradation RNAi: - Dicer cleaves trigger dsRNA - siRNAs obtained. - siRNA stabilized by Argonaute proteins in RISC. - Like miRNA, siRNAs scan the entire transcriptome (mRNAs). - Binds to complimentary sequence. - Piwi domain cleaves mRNA by Slicer activity. - mRNA degraded. miRNAs MicroRNA May have multiple targets, usually control genenetworks. For humans: often found in fragile sites and genomic regions involved ion cancers. Heterochronic Timing is off. Larval stage forever, or skipped, etc. Lin-4 Encodes small RNAs with antisense complementarity to lin-14. Lin-4 base pairs to 7 parts of lin-14. Mismatches helps dodge slicing machinery. Lin-4 mutants have weird timing. P bodies Store mRNA, dodge translation machinery. Gel like. Biophysical properties favour interactions between RNA and Protein. Have these activities: - Decapping & mRNA degradation - Storing mRNA until translation - Aid in translational repression by miRNA miRNA cascade (ENDOGENOUS) - Lin-4L precursor folds like a hairpin, making dsRNA. - Matures into lin-4S. Similar to an siRNA. - Lin-4 has partial complimentarity with lin14 3’UTR. - Prevents Slicer activity BUT represses lin-14. In vertebrates: - Drosha cleaves pri-miRNA transcript into pre-miRNA hairpin - Exp5 brings it to cytoplasm - Dicer matures it into siRNA duplex by cleaving off hairpin - siRNA bind Argo2, assembles into RISK - RISK scans mRNAs miRNA mediated silencing. No slicer activity! Option 1: miRNAs prevent translational initiation Option 2: miRNAs prevent PIC assembly Option 3: (strongest) - miRNAs bind at 3’, recruit Deadenylation complex. - Poly-A tail removes - mRNA is destabilized and degraded - Reduction in translational initiation - May be coupled to decapping - mRNA is destabilized but NOT degraded! o Controlled repression The seed defines target for miRNA Nucleotides 2 to 7 of miRNA - Stronger base pairing brings RISK to UTR. - 3’ UTRs do not have ORF, highly structured RNA balls. - RISK may not get through UTR Let-7 RAS regulation Let-7 A microRNA. Can act as a tumor suppressor. Highly conserved from flies to humans. Controls RAS expression in Human Cells. Down-regulated in most tumors. C. elegans let-7 mutants keep dividing, don’t differentiate. RAS miR-17-92 Oncogenic microRNA Increased expression in lymphocytes linked with Lymphoproliferative disease and autoimmunity in mice. Bcl2 Let 7 seeds bind RAS UTRs This relationship is highly conserved. Let-7 lowers RAS expression in humans Let-7 is downregulated in tumors, RAS goes up. miRNAs and Cancer miRNAs can be tumor suppressors or oncogenes. Context-dependent! **Recall: Tumor suppressor stops cancer genes, proto-oncogenes can become oncogenes. TS repressive, Oncogene dominant. c-Myc and miR-17~92 Polycistron. 4 families (mir17/mir20), (mir18), mir19, mir92. 6 miRNAs Amplicon Causes genomic amplification, one source, many targets. c-Myc Encodes a TF. Activates miR-17-92 Cluster/Polycistron A group of microRNAs expressed from a single transcription unit. Pri-mR-17~92 Has many pre-miRNAs attached, gives birth to 6 miRNAs. Members have different targets that converge on thesame functions. miRNA family Share the same seed! Often leads to similar function. miR-19 Oncogeniccomponent of mir-17~92 Selective pressure for it, amplified in many cancers. Controls PTEN, more PTEN=Reduced apoptosis by reverting PI3K activity. miR-19 is a repressor of a repressor! Other members control BIM o
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